Different studies have estimated cities’ contribution to total greenhouse gas (GHG) emissions at between forty and seventy percent. According to the so-called Compact City Approach, high density and centrality should lead to low GHG. This study compares the effect of the urban density and spatial structure (monocentrism, polycentrism, and dispersion) of the main U.S. cities on their greenhouse gas emissions from mobility and housing. The estimated models include control variables in order to improve the statistical adjustment, these variables are grouped into three categories: basic controls as temperature and Gross Domestic Product (GDP); historical-demographic controls since 1900; and geographic-urban planning controls. The results detect an environmentally positive effect, albeit a moderate one, associated with monocentric and polycentric spatial structures as compared to dispersed structures. Within the tradition of urban planning, these results can be used as an argument to stop the dispersed decentralization of cities. However, the efficacy of some policies encouraging density should be accompanied by specific policies which increase the energy efficiency of housing and promote the use of public transport.